Knowledge Centre



STABILITY STUDY

Stability study of a drug product

Stability is the extent to which a product retains within specified limits and throughout its period of storage and use the same properties and characteristics that it possessed at the time of its manufacture.

Temperature and humidity stability

It is always better to check the stability of a product with combined effect of temperature and humidity rather than temperature or humidity alone because the regulatory requirement is always proving stability with a combination of temperature and humidity.

The stability study of a product is done in open exposure condition and closed packing condition. The stability testing explained below is performed at prototype development stage.


Closed pack stability
  • Choose the market pack for your product such as HDPE container or blister pack.
  • Pack the required number of units in HDPE bottle or blister pack. Normally the number of units should be similar to the number of units in innovator pack. Insert a silica gel or molecular sieve sachet or cotton or rayon if the product is going to be marketed with these materials.
  • The HDPE bottles can be sealed with CRC cap or normal cap with wad by using induction cap sealer.
  • Keep the samples at time point- e.g. at 40 ̊ C / 75% RH for 15 days,1 month,2 months,3 months and if required 6 months. At 25 ̊ C /60% RH for 1 month,2 months,3 months and if required 6 months.
  • At the end of the exposed period, the samples should be examined for any changes in

Physical properties (e.g., appearance, color of the product, hardness, thickness, disintegration time, LOD/water content, polymorphic change) etc.

  • In case of appearance of the drug product, check for roughness, surface crack, edge erosion e.t.c. There should not be a significant change in the color of the product.
  • For LOD, crush tablets equivalent to 1 gm of blend and check the LOD at 60 ̊ C or 105 ̊ C depending on the melting point of the drug substance. The LOD should not change significantly from the initial time point.

Chemical properties (Assay, dissolution and related substances)

  • Analyze one month sample of 40 ̊ C / 75% RH condition. Check for the changes in results compared to initial sample such as rise in impurities, change in dissolution profile.
  • If there is a significant change in the results at 40 ̊ C / 75% RH in first 1 month itself then the formulation may need either change of excipients or formulation process.
  • When the sample at 40 ̊ C / 75% RH condition show significant change, analyze 25 ̊ C /60% RH samples for further verification.

Open exposure stability

Open exposure stability of a drug product is done to observe the stability of product under harsh environmental condition .This is not a regulatory requirement but it can be done on R&D batches to gain confidence on the stability of the API in the drug product. Open exposure of the formulation will give an idea how best the selection of excipients is done for the formulation.

  • Pack the required number of units in HDPE bottle and wrap the mouth of the bottle with parafilm in order to protect the samples from falling out of bottle and getting contaminated. Make small holes in parafilm.
  • There is no need to keep any silica gel or cotton in the bottle.
  • Label the sample properly. Load the sample for up to 1 month in stability chamber at 40 ̊ C / 75% RH condition.
  • Withdraw the samples at time points 1 week, 2 weeks and 4 weeks. Analyze the samples for the impurity level and / or assay. If there is a drastic change in the impurity level/assay compared to the results of 40 ̊ C / 75% RH closed packing condition then a formulation may need either change of excipients or formulation process.

Photostability study of a drug product

Normally, the photostability studies on drug products should be carried out in a sequential manner starting with testing the fully exposed product then progressing as necessary to the product in the immediate pack and then in the marketing pack. Testing should progress until the results demonstrate that the drug product is adequately protected from exposure to light.


Light source

Sample should be exposed to both the cool white fluorescent and near ultraviolet lamp.

A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) and

A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm.

Samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours.
(Reference: Q1B- ICH guidelines)


Temperature

The formulator should maintain an appropriate control of temperature to minimize the effect of localized temperature changes.
(Reference: Q1B- ICH guidelines)


Selecting the locations for samples in photostability chamber
  • Lux meter can be used to read the intensity of a light at a particular location in the photostability chamber.
  • Insert the probe of lux meter through the hole provided in the chamber, keep it on any location on the tray and close the hole with the cap.
  • Switch on the white fluorescent and UV lamps. Check the reading on the lux meter.
  • Note the reading on the sticker label. Switch off the lamps, open the chamber and stick the label at the probe point.
  • Remove the probe, keep it on different location on the tray in the chamber and repeat the above procedure.
  • Make sure that the chosen locations have nearly similar intensity to minimize the variations in exposure of the light to test and control samples. With nearly similar intensity of light, test and control samples can be analyzed on the same day.
  • Three samples are required to be prepared for drug product.

Required number of tablets / capsules in

  • Open Petridish (Test sample),
  • Closed Petridish (Test sample),
  • Closed petridish covered with black polybag (control sample)

Calculating duration of light exposure to samples

Let us assume that the intensity at particular location in the chamber for test sample is 4430 lux. Choose another location having light intensity of nearly similar range for control sample (for example 4500 lux).

For the test sample to get exposed to 1.2 million lux hr, it has to be kept in photostability chamber for the following number of days

4430 lux x Y = 1.2 x 10 6 lux hr
Y = 1.2 x 10 6 lux hr / 4430 lux = 270.88 hr = 271 hr

Converting hours into number of days = 271 hr/24 hr = 11.29 days ~ 11.5 days

Similarly, for the control sample to get exposed to 1.2 million lux hr, it has to be kept in photostability chamber for the following number of days

4500 lux x Y = 1.2 x 10 6 lux hr
Y = 1.2 x 10 6 lux hr / 4500 lux = 266.66 hr = 267 hr

Converting hours into number of days = 267 hr/24 hr = 11.12 days ~ 11.5 days

(Where as Y is the total hours required for light exposure)

From above example both test and control samples having exposed to nearly similar light intensity can be analyzed on the same day.


Presentation of Samples
  • Possible interactions between the samples and any material used for containers or for general protection of the sample should also be considered and eliminated wherever not relevant to the test being carried out.
  • The samples should be positioned to provide maximum area of exposure to the light source. For example, tablets, capsules, etc., should be spread in a single layer.
  • If direct exposure is not practical (e.g., due to oxidation of a product), the sample should be placed in a suitable protective inert transparent container (e.g., quartz).
  • If testing of the drug product in the immediate container or as marketed is needed, the samples should be placed horizontally or transversely with respect to the light source for the most uniform exposure of the samples. Some adjustment of testing conditions may have to be made when testing large volume containers (e.g., dispensing packs).
    (Reference: Q1B- ICH guidelines)

Analysis of Samples
  • At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity or color of solution, dissolution / disintegration for dosage forms such as capsules, etc.) and for assay and degradants by a method suitably validated for products likely to arise from photochemical degradation processes.
  • When powder samples are involved, sampling should ensure that a representative portion is used in individual tests.
  • For solid oral dosage form products, testing should be conducted on an appropriately sized composite of, for example, 20 tablets or capsules.
  • The analysis of the exposed sample should be performed concomitantly with that of protected samples used as dark controls.
    (Reference: Q1B- ICH guidelines)

Conclusion

If the sample degrades beyond the acceptance limits then precautionary measures need to be taken during dispensing of API, formulation development and Analysis.

To avoid photo degradation, perform formulation and analysis under sodium vapour lamp.

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